HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure

Trieb, Markus; Rainer, Florian; Stadlbauer, Vanessa; Douschan, Philipp; Horvath, Angela; Binder, Lukas; Trakaki, Athina; Knuplez, Eva; Scharnagl, Hubert; Stojaković, Tatjana; Heinemann, Ákos; Mandorfer, Mattias; Paternostro, Rafael; Reiberger, Thomas; Pitarch, Carla; Amorós, Àlex; Gerbes, Alexander L.; Caraceni, Paolo; Alessandria, Carlo; Moreau, Richard; Clària, Joan; Marsche, Gunther; Stauber, Rudolf

doi:10.1016/j.jhep.2020.01.026

Cited by 66 publications

(75 citation statements)

References 44 publications

(45 reference statements)

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“…ApoA1 is the main stabilizing apolipoprotein of HDL (34). ApoA1 itself can deactivate bacterial endotoxins and mitigate the TNF-alpha production after LPS or LTA exposure (35,36).…”

Section: Discussionmentioning

confidence: 99%

Arylesterase Activity of HDL Associated Paraoxonase as a Potential Prognostic Marker in Patients With Sepsis and Septic Shock—A Prospective Pilot Study

et al. 2020

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Background: High-density lipoprotein (HDL) plays an essential role in the immune system and shows effective antioxidative properties. We investigated correlations of lipid parameters with the sequential organ failure assessment (SOFA) score and the prognostic association with mortality in sepsis patients admitted to intensive care unit (ICU). Methods: We prospectively recruited consecutive adult patients with sepsis and septic shock, according to sepsis-3 criteria as well as non-sepsis ICU controls. Results: Fifty-three patients with sepsis (49% with septic shock) and 25 ICU controls without sepsis were enrolled. Dyslipidemia (HDL-C < 40 mg/l) was more common in sepsis compared to non-sepsis patients (85 vs. 52%, p = 0.002). Septic patients compared to controls had reduced HDL-C (14 vs. 39 mg/l, p < 0.0001), lower arylesterase activity of the antioxidative paraoxonase of HDL (AEA) (67 vs. 111 mM/min/ml serum, p < 0.0001), and a non-significant trend toward reduced cholesterol efflux capacity (9 vs. 10%, p = 0.091). We observed a strong association between higher AEA and lower risk of 28-day [per 10 mM/min/ml serum increase in AEA: odds ratio (OR) = 0.76; 95% CI, 0.61-0.94; p = 0.01) and ICU mortality (per 10 mM/min/ml serum increase in AEA: OR = 0.71, 95% CI, 0.56-0.90, p = 0.004) in the sepsis cohort in univariable logistic regression analysis. AEA was confirmed as an independent predictor of 28-day and ICU mortality in multivariable analyses. AEA discriminated wellregarding 28-day/ICU mortality in area under the receiver operating characteristic curve (AUROC) analyses. In survival analysis, 28-day mortality estimates were 40 and 69% with AEA ≥/< the 25th percentile of AEA's distribution, respectively (log-rank p = 0.0035). Reisinger et al. Arylesterase Activity in Sepsis Conclusions: Both compositional and functional HDL parameters are profoundly altered during sepsis. In particular, the functionality parameter AEA shows promising prognostic potential in sepsis patients.

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“…ApoA1 is the main stabilizing apolipoprotein of HDL (34). ApoA1 itself can deactivate bacterial endotoxins and mitigate the TNF-alpha production after LPS or LTA exposure (35,36).…”

Section: Discussionmentioning

confidence: 99%

Arylesterase Activity of HDL Associated Paraoxonase as a Potential Prognostic Marker in Patients With Sepsis and Septic Shock—A Prospective Pilot Study

et al. 2020

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“…Cholesterol efflux capacity is markedly impaired in septic patients 29,30 and physical inactivity, inadequate exercise and an overall sedentary lifestyle are associated with impaired immune response 31 and increased risk of viral infections 31 and sepsis 32,33 . Low levels of HDL-cholesterol and low-density lipoprotein-cholesterol are associated with poor clinical outcomes and increased risk of infectious disease and survival, respectively [34][35][36] , while in critically ill and especially in septic patients, a reduction in lipid and lipoprotein levels has been well documented 37 , in particular apoA-I, apoA-II 15,30 , HDL and low-density lipoprotein 30,38,39 . Prolonged bedrest increases the risk of hospital-acquired pneumonia, which is often caused by bacterial infection 3 .…”

Section: Discussionmentioning

confidence: 99%

Prolonged bedrest reduces plasma high-density lipoprotein levels linked to markedly suppressed cholesterol efflux capacity

Trakaki

Scharnagl

Trieb

et al. 2020

Sci Rep

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Recent observations strongly connect high-density lipoproteins (HDL) function and levels with coronary heart disease outcomes and risk for infections and sepsis. To date, our knowledge of factors determining this connection is still very limited. The immobility associated with prolonged bedrest is detrimental to health, affecting several systems, including the cardiovascular, pulmonary, gastrointestinal, musculoskeletal and urinary. Effects of prolonged bedrest on the composition and functional properties of HDL remain elusive. We evaluated metrics of HDL composition and function in healthy male volunteers participating in a randomized, crossover head-down bedrest study. We observed that HDL cholesterol efflux capacity was profoundly decreased during bedrest, mediated by a bedrest associated reduction in plasma levels of HDL-cholesterol and major apolipoproteins (apo) apoA-I and apoA-II. Paraoxonase activity, plasma anti-oxidative capacity and the activities of lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein were not affected. No change was observed in the content of HDL-associated serum amyloid A, a sensitive marker of inflammation. Resistive vibration exercise countermeasure during bedrest did not correct impaired cholesterol efflux capacity and only tended to increase arylesterase activity of HDL-associated paraoxonase. In conclusion, prolonged bedrest reduces plasma HDL levels linked to markedly suppressed HDL cholesterol efflux capacity. Resistive vibration exercise during bedrest did not correct HDL levels and impaired cholesterol efflux capacity.

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“…More recently it has been also shown that baseline levels of HDL were significantly lower in patients with stable cirrhosis than in healthy subjects, and this predicted the development of liver-related complications independently of MELD score. 15 In experimental models, as well as in patients with severe cirrhosis, recombinant HDL infusion was able to reduce concentration of pro-inflammatory cytokines by neutralizing circulating LPS. 13,14 In order to investigate the mechanism(s) underlying the protective role exerted by HDL in iVP16-LXRα mice in vivo, we performed in vitro experiments by using cell lines of the two main liver cell phenotype involved in the release of pro-fibrogenic signals, ie KCs and hepatocyte,, 1,3,4 although a role of LSEC can also be hypothesized.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14] In patients with stable cirrhosis, baseline levels of HDL were significantly lower compared to controls predicting the development of liver-related complications independently of MELD. 15 Despite these lines of evidence, HDL role in chronic liver diseases has not been fully elucidated and the use of currently available pan-LXR agonists (that activate both isoforms), induces hepatic steatosis and hypertriglyceridemia by LXRαmediated induction of sterol regulatory element-binding protein 1 (SREBP-1)c in hepatocytes. 4,16 Therefore, alternative strategies have been considered, especially in the field of atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

HDL cholesterol protects from liver injury in mice with intestinal specific LXRα activation

Pierantonelli¹,

Lioci

Gurrado

et al. 2020

Liver International

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Background and aims Liver X receptors (LXRs) exert anti‐inflammatory effects even though their hepatic activation is associated with hypertriglyceridemia and hepatic steatosis. Selective induction of LXRs in the gut might provide protective signal(s) in the aberrant wound healing response that induces fibrosis during chronic liver injury, without hypertriglyceridemic and steatogenic effects. Methods Mice with intestinal constitutive LXRα activation (iVP16‐LXRα) were exposed to intraperitoneal injection of carbon tetrachloride (CCl4) for 8 weeks, and in vitro cell models were used to evaluate the beneficial effect of high‐density lipoproteins (HDL). Results After CCl4 treatment, the iVP16‐LXRα phenotype showed reduced M1 macrophage infiltration, increased expression M2 macrophage markers, and lower expression of hepatic pro‐inflammatory genes. This anti‐inflammatory effect in the liver was also associated with decreased expression of hepatic oxidative stress genes and reduced expression of fibrosis markers. iVP16‐LXRα exhibited increased reverse cholesterol transport in the gut by ABCA1 expression and consequent enhancement of the levels of circulating HDL and their receptor SRB1 in the liver. No hepatic steatosis development was observed in iVP16‐LXRα. In vitro, HDL induced a shift from M1 to M2 phenotype of LPS‐stimulated Kupffer cells, decreased TNFα‐induced oxidative stress in hepatocytes and reduced NF‐kB activity in both cells. SRB1 silencing reduced TNFα gene expression in LPS‐stimulated KCs, and NOX‐1 and IL‐6 in HepG2. Conclusions Intestinal activation of LXRα modulates hepatic response to injury by increasing circulating HDL levels and SRB1 expression in the liver, thus suggesting this circuit as potential actionable pathway for therapy.

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HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure

Cited by 66 publications

References 44 publications

Arylesterase Activity of HDL Associated Paraoxonase as a Potential Prognostic Marker in Patients With Sepsis and Septic Shock—A Prospective Pilot Study

Arylesterase Activity of HDL Associated Paraoxonase as a Potential Prognostic Marker in Patients With Sepsis and Septic Shock—A Prospective Pilot Study

Prolonged bedrest reduces plasma high-density lipoprotein levels linked to markedly suppressed cholesterol efflux capacity

HDL cholesterol protects from liver injury in mice with intestinal specific LXRα activation

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